This paper reports evidence of the very unusual differential cell sensitivity toward compositionally similar surfaces obtained by irradiation treatments, In particular, we studied the adhesion, proliferation, and spreading of normal human dermal fibroblasts onto poly(hydroxymethylsiloxane) surfaces modified by either O-2 plasma (aged in air or water) or 6 keV Ar+ beams. The cell response ranges from relatively low adhesion and scarce viability for O-2-plasma-treated surfaces to a complete cell confluence and optimal spreading and proliferation in the case of 6-keV Ar+ beams. Two different types of altered layers have been identified for the two irradiation techniques, respectively consisting in an amorphous SiCxOy(H-z) phase, produced in the ion-mixing process in the collision cascades induced by 6-keV Ar+ beams, and an almost pure amorphous SiO2-like phase, produced by the highly selective removal of carbon-containing volatile species in the O-2 plasma. The observed differential cell response in the case of various plasma-treated surfaces is related to the relative increase of surface free energy. The peculiar optimal cell response onto Ar+-irradiated surfaces is instead assigned to the peculiar electronic structure and related electrical properties of the ion mixed layer.